tbuckley/cabot-search huggingface dataset:
Abstract 3580: Noninvasive immuno-PET imaging of CD8+T cell behavior in tumor bearing mice models treated with SAR444245
Authors: Sebastion d'Heilly, Fabrice Tirode, Maxime Gaulin, Dudzicki Anne, Guillaume Bluet, Stéphane Guerif, Francis Descamps, Peter Casteels, Xiangming Li, Rui Wang, Robin Meng, Erwan Jouannot
Journal: Cancer Research (2023)

Abstract SAR444245 (formerly THOR-707) is a site-specific pegylated recombinant human IL-2 molecule which blocks IL-2R alpha-binding while retains near-native affinity for beta/gamma IL-2 receptor subunits. SAR444245 reduces B16-F10 tumor proliferation in C57BL/6 mice and induces a short transient migration of CD8+ T and NK cells from peripheral blood to lymphoid organs before a strong proliferation (Ptacin et al, Nat Commun 2021). Here we report CD8+ T cells imaging post SAR444245 as monotherapy in naive and tumor bearing mice using nuclear imaging. An anti-murine CD8+ PET probe was injected in mice 24 hours post SAR444245 administration and nuclear imaging was performed at different times over 6 days. In C57BL/6 naive and in poorly immunogenic B16-F10 tumor bearing animals, images reveal a decreased Standardized Uptake Value (SUV) within blood in treated animals at 3mg/kg compared to control ones. In parallel, blood SUV Ratio (SUVR) increases within spleen, lymph nodes and thymus after SAR444245 injection compared to control mice. On tumor site, a stronger SUVR is measured at 144 hours post injection in SAR444245 treated group than in the control group. A dose escalation ranging from 1 to 6 mg/kg of SAR444245 was performed in highly immunogenic CT26 tumor bearing animal. Blood SUV decreases in the treated groups compared to the control group. In lymphoid organs, all SUVR increase at 144 hours post injection in the treated groups compared to the control one. In CT26 tumors, a slight increase of the SUVR is observed for groups treated at 3 and 6 mg/kg. In parallel, a pronounced reduction of tumor growth is observed in the treated group at 6mg/kg. These studies non-invasively confirm the mode of action of SAR444245 with a rapid relocation of CD8+ T cells from peripheral blood to lymphoid organs and tumor site. Citation Format: Sebastion d'Heilly, Fabrice Tirode, Maxime Gaulin, Dudzicki Anne, Guillaume Bluet, Stéphane Guerif, Francis Descamps, Peter Casteels, Xiangming Li, Rui Wang, Robin Meng, Erwan Jouannot. Noninvasive immuno-PET imaging of CD8+T cell behavior in tumor bearing mice models treated with SAR444245. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3580.
Abstract 4502: Aptamer conjugated prostate specific membrane antigen (PSMA) targeting nanobees for prostate cancer prevention and therapy
Authors: Islam Rady, Sayed Bakry, Fatma Abou El-Azm, Hasan Mukhtar
Journal: Cancer Research (2023)

Abstract Melittin (MEL), a major peptide component of bee venom (BV), has shown chemopreventive as well as chemotherapeutic effects against many cancers in preclinical model systems. However, its applicability to humans has met with limited success due to several issues including its toxicity, nonspecificity, degradation, inefficient systemic delivery and limited bioavailability. Earlier, the concept of "nanochemoprevention" i.e. the use of nanotechnology to improve the outcome of cancer chemoprevention is introduced. Then, "non-targeted nanobees" i.e. nanoformulated mellitin is developed to exhibit excellent anti-prostate cancer efficacy in vitro and in animal models coining the concept as ‘Nanobee- Chemoprevention’. Here, we are extending this work and developed nanobees targeted with small molecular entities (A10 2′-fluoropyrimidine RNA aptamers (Apt)), able to bind to prostate specific membrane antigen (PSMA), a transmembrane protein that is overexpressed in prostate cancer (PCa) and evaluated their efficacy in preclinical studies. The Apt-Nanobees led to an enhanced anti-proliferative activity in PCa cell lines compared to the free melittin. The behavior of Apt-Nanobees in modulating apoptosis and cell-cycle, was also determined. Then, in vivo experiments, in mouse xenograft model of prostatic tumor using nanobees with a model of targeted nanosystems, were conducted. The obtained data supported our hypothesis of targeted nanobees enhanced the bioavailability and limited unwanted toxicity of melittin, thus leading to a significant potential for probable clinical outcome. Citation Format: Islam Rady, Sayed Bakry, Fatma Abou El-Azm, Hasan Mukhtar. Aptamer conjugated prostate specific membrane antigen (PSMA) targeting nanobees for prostate cancer prevention and therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4502.
Abstract 600: Tumour and local lymphoid tissue interaction determines prognosis in high grade serous ovarian cancer
Authors: Haonan Lu, Georg Wengert, Hantao Lou, Reema Paudel, Naina Patel, Saral Desai, Bill Crum, Kristofer Linton-Reid, Mitchell Chen, Dongyang Li, Jacey Ip, Francesco Mauri, David J. Pinato, Andrea Rockall, Susan J. Copley, Sadaf Ghaem-Maghami, Eric O. Aboagye
Journal: Cancer Research (2023)

Abstract Tertiary lymphoid structure (TLS) is an ectopic lymphoid organ found in some tumors. The presence of TLS is recently proposed as a predictive biomarker for immune checkpoint inhibitors (ICI) in mutation-driven tumors. It is also associated with prognosis in copy number-driven tumors, including high grade serous ovarian cancer (HGSOC), although the function of TLS and its interaction with copy-number alterations in HGSOC is not fully understood. In the current study, we comprehensively analyze immune profile, copy number profile and quantitative imaging profile from 242 HGSOC patients (HH cohort), and combine these with two public single cell RNA-sequencing datasets (Lambrechts cohorts; n=9, 29,999 cells). TLS-high HGSOC patients show significantly better progression free survival in both HH and TCGA cohorts. We show that presence of TLS in HGSOC tumors is associated with B-cell maturation, resulting in higher and more specific immunoglobulin production; TLS also leads to more cytotoxic tumor-specific T-cells activation and proliferation. Through integrated analysis of single cell RNA-sequencing and whole exome sequencing data, we reveal that the copy number loss of IL15 and CXCL10 may limit TLS formation in HGSOC; we also propose a list of genes that may dysregulate TLS function. A candidate gene, DCAF15, is found to confer resistance to NK-mediated cytotoxicity in HGSOC cell lines. Lastly, we develop a radiomics-based signature to predict presence of TLS, which independently predicts PFS in both HGSOC patients and ICI-treated NSCLC patients. Overall, we reveal that TLS coordinates intratumoral B-cell and T-cell response against HGSOC tumor, while cancer genome evolves to counteract TLS formation and function. Citation Format: Haonan Lu, Georg Wengert, Hantao Lou, Reema Paudel, Naina Patel, Saral Desai, Bill Crum, Kristofer Linton-Reid, Mitchell Chen, Dongyang Li, Jacey Ip, Francesco Mauri, David J. Pinato, Andrea Rockall, Susan J. Copley, Sadaf Ghaem-Maghami, Eric O. Aboagye. Tumour and local lymphoid tissue interaction determines prognosis in high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 600.
Abstract 390: A comparison of the activity of the quadruplex-targeting experimental drugs QN-302 and CX-5461 (pidnarulex) in wild-type and gemcitabine-resistant pancreatic cancer cell lines
Authors: Ahmed Ahmed, Tariq Arshad, Stephen Neidle
Journal: Cancer Research (2023)

Abstract The compound QN-302, a tetra-substituted naphthalene diimide (ND) derivative has been designed as a potent compound for targeting quadruplex sequences in cancer genes. It has single-digit nM anti-proliferative activity in a panel of human pancreatic cancer (PDAC) cell lines (Ahmed et al., ACS Med Chem Lett, 2020, 11, 1634-1644). It also has significant anti-tumor activity in xenograft, orthotopic and genetic (KPC) models for PDAC. Its mode of action involves the targeting of quadruplex (G4)-forming sites in promoter regions of cancer-associated genes, where their prevalence is over-represented compared to other genes. The structurally unrelated compound CX-5461 has also been reported to be a G4-binding agent, with selective activity in BRCA1/2 deficient cells and tumors (Xu and Hurley, Bioorg Med Chem Lett. 2022; Xu et al., Nat Commun, 2017). It is currently in early-stage clinical trials in breast and other solid cancers with deficiencies in DNA repair (Hilton et al., Nat Commun. 2022). We have previously reported that a precursor to QN-302, the tri-substituted naphthalene diimide compound CM03, is highly active in both wild-type and gemcitabine-resistant PDAC cell lines (Ahmed et al, Sci Rep, 2020). This is explained by the finding using whole-genome transcriptome analysis that the CM03-sensitive genes are largely unaffected in the resistant lines. We now report that the clinical candidate compound QN-302, which is 10-fold more potent than CM03, retains its potency in both MIA-PACA2 and PANC-1 PDAC cell lines with &amp;gt;1000-fold increase in gemcitabine resistance. This is also the case for CX-5461, although this compound is 50-100 times less potent, with GI50 values of 83-95 nM in cell proliferation assays treated for 96 h. Gemcitabine either alone or in combination is still a mainstay of current PDAC treatment. Resistance to gemcitabine is common and is a major contributor to the poor outcomes for most PDAC patients. The ability of QN-302 to retain activity in chemo-resistant PDAC cell lines suggests that it will offer significant advantage in the clinic over gemcitabine-based therapies. QN-302 is bio-available at therapeutic doses and is well tolerated at these levels in animal models. It is being developed for clinical evaluation by Qualigen Therapeutics Inc and is currently at the pre-IND stage. Citation Format: Ahmed Ahmed, Tariq Arshad, Stephen Neidle. A comparison of the activity of the quadruplex-targeting experimental drugs QN-302 and CX-5461 (pidnarulex) in wild-type and gemcitabine-resistant pancreatic cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 390.
Abstract 6666: Multispectral imaging to detect immune phenotypes in pre and post therapy breast cancer patient specimens
Authors: Bhavika Patel, Stephanie Allen, Brenna Dennison, Jacob Stapleton, Roni Archuleta, Mary Lou Rath, Navi Mehra, Sameer S. Talwalkar
Journal: Cancer Research (2023)

Abstract The immune microenvironment is an important component in cancer therapy. Immune cells can encourage tumor growth, leading to disease progression. A high number of immune cells may be predictive of disease prognosis and response to therapies. Therefore, understanding the immune cell phenotypes present within cancerous tissue can be valuable in developing strategies that aid in the treatment of cancer. In this study, we analyzed pre-and post-therapy samples from breast cancer patients, treated with neoadjuvant chemotherapy, using a 6-plex immunofluorescence assay which included clinically relevant immuno-oncology biomarkers (FoxP3, PD-L1, PanCK, CD4, CD8 and CD163). This assay was developed and optimized in-house prior to testing the cohort. Endpoints for this analysis were characterization of the tumor microenvironment and analysis of the individual immune cell subsets pre and post treatment. Staining was completed on the Leica Bond RX autostainer (Leica Biosystems) and slides were scanned using the PhenoImager™ Fusion (Akoya Biosciences). Using Visiopharm® software, the multiplex phenotyping module was used to analyze the high dimensional human tissue and cell phenotypes were detected using artificial intelligence. Qualitative and quantitative results revealed a change in immune cell phenotypes between pre- and post-therapy samples. These included an increase in intra-tumoral and stromal T cells, no significant difference in PD-L1 positive cells, and an increase in the FOXP3 positive T cells in post-treatment samples. Our data provides insights into the development and application of multispectral imaging for characterization of tumor microenvironment and its dynamics before and after treatment in breast cancer. This can be applied to other cancer types and can aid in making treatment decisions. Citation Format: Bhavika Patel, Stephanie Allen, Brenna Dennison, Jacob Stapleton, Roni Archuleta, Mary Lou Rath, Navi Mehra, Sameer S. Talwalkar. Multispectral imaging to detect immune phenotypes in pre and post therapy breast cancer patient specimens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6666.
Abstract 6582: A path to sustainability for the National Cancer Institute's Cancer Research Data Commons
Authors: Juergen A. Klenk, Angela Maggio, Bhavani S. Singh, Erin N. Byrne, Erika Kim, Tanja M. Davidsen
Journal: Cancer Research (2023)

Abstract Purpose: The volume of data produced by the biomedical research community continues to grow rapidly. Efficient collection, curation, and sharing of these data are expected to enable researchers to synthesize larger datasets and apply novel methods to discover new patterns for diagnosis, treatment, and care of disease. Consequently, data platforms that support these functionalities have become an important instrument for the biomedical research community. The National Cancer Institute’s (NCI’s) Cancer Research Data Commons (CRDC) is a data platform for the cancer research community that provides cloud-based, secure storage and analytic tools for cancer data, including genomics, proteomics, imaging, and clinical trial data. CRDC has been funded by multiple sources, including the Beau Biden Cancer Moonshot program. Achieving long-term sustainability of the CRDC program is the focus of our study. Methods: We applied a Financial Operations (FinOps) framework to map all costs to functionalities provided by the CRDC, including processes such as data intake, storage, compute, user support, and project management. We established a comprehensive financial baseline for the operations of the CRDC, identified opportunities for optimization across multiple dimensions (people, processes, technology), projected future costs based on trends for cancer data, and evaluated sustainability under defined funding scenarios. Results: We identified 15 recommendations for optimization of the CRDC, including automation and centralization of core services (e.g., intake, curation, indexing), optimization of storage (e.g., compression, archiving), and harmonization of common services across the CRDC components (e.g., common architecture, governance). If implemented, we could demonstrate that these recommendations offer a path to long-term sustainability of the CRDC program under a variety of funding scenarios. Conclusion: Data platforms such as the CRDC will see rapid increases in operational costs due to the growing data volumes and demand from researchers. Optimizing governance and operational frameworks will result in efficiency gains that can ensure long-term sustainability. Taking these steps will be critical to provide the necessary infrastructure to advance the field of data-driven biomedical research. Citation Format: Juergen A. Klenk, Angela Maggio, Bhavani S. Singh, Erin N. Byrne, Erika Kim, Tanja M. Davidsen. A path to sustainability for the National Cancer Institute's Cancer Research Data Commons. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6582.
Abstract 1681: The alternative mechanism of Src inhibition in colon cancer cells
Authors: Yi-Wen Lu, Xiang-Ling Hou, Yen-Tse Lu, Chia-Wen Lin, Chien-Chi Huang, Wei-Ting Chao
Journal: Cancer Research (2023)

Abstract In colon cancer, Src showed the high expression in tumor cells and was known as an important migration marker that plays the role in coordinate with many important cellular signal pathways. According to previous studies, cell viability and migration ability can be inhibited by Src inhibitor, Dasatinib. However, the clinical study demonstrated the survival rate has no significant increase in Dasatinib treatment. Therefore, we want to figure out what is the real function of Src in colon cancer cell in this study. HT-29, colon cancer cell with epithelial cell morphology was used in the study. After treated with Dasatinib, cells were followed by reattachment experiment. Then the cell growth, migration ability, signaling pathway transition, molecular localization and expressions were analyzed. The results showed Src inhibition can reduce EGFR activation on cell-cell contacts and increased Akt phosphorylation upon EGF stimulation. We further found Dasatinib has limited effect on cell toxicity, however, can be the selector to separate two cell populations, Dasatinib sensitive (DSTS) and Dasatinib resistance (DSTR) cells, interestingly, the DSTS cells were grown as colony phenotype efficiently and majorly through EGFR/AKT pathway. Meanwhile, DSTR was demonstrated the promotion of collective cell migration ability by EGFR/Ecad pathway. The results of this study suggested Src activity plays novel role in switch EGFR/Akt and EGFR/Ecad pathways in colon cancer cells and harboring different strategies to survive, therefore, the alternative resistance mechanism of Src inhibitor in colon cancer cells may need be concerned in clinical application. Citation Format: Yi-Wen Lu, Xiang-Ling Hou, Yen-Tse Lu, Chia-Wen Lin, Chien-Chi Huang, Wei-Ting Chao. The alternative mechanism of Src inhibition in colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1681.
Abstract 3551: Single-cell characterization of pediatric T-cell acute lymphoblastic leukemia transcriptomes
Authors: Irina Pushel, Byunggil Yoo, Daniel Louiselle, Margaret Gibson, Midhat S. Farooqi, Keith August
Journal: Cancer Research (2023)

Abstract Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is a rare cancer with a diverse set of causative genomic abnormalities. The variety and limited characterization of genomic mechanisms underlying this disease presents a unique challenge for the development of improved treatments for these patients. Using the 10x Genomics Chromium system, we have generated single-cell gene expression (scRNA) and chromatin accessibility (scATAC) data for blood and/or bone marrow samples collected at diagnosis from eight pediatric T-ALL patients. We sequenced 21,669 high-confidence cells and performed normalization and downstream analysis using the Seurat v4.0.2 package in R 4.0.3. Our data show that patient cancer cells show highly individual transcriptomes and are often characterized by combinatorial expression patterns of genes including MEF2C, BCL11B, HOXA9, NKX2-1, and LMO2, which have been previously implicated for their roles in various T-ALL subtypes. Additionally, we observe that each patient has a unique ratio of cancer cells with a CD4+ T-cell, CD8+ T-cell, and hematopoietic stem cell-like identity, which may be linked to treatment response and patient outcome. This dataset represents one of the first forays into exploring the biology of pediatric T-ALL at the single-cell level. Our comparative analysis of patient cancer cells reveals novel insights into the transcriptional and chromatin-related for distinct subsets of pediatric T-ALL cases, paving the way for future treatment selection and drug development to improve outcomes for these patients. Citation Format: Irina Pushel, Byunggil Yoo, Daniel Louiselle, Margaret Gibson, Midhat S. Farooqi, Keith August. Single-cell characterization of pediatric T-cell acute lymphoblastic leukemia transcriptomes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3551.
Abstract 3610: Prenylated PALM2 promotes the migration of esophageal squamous cancer cells through activating ezrin
Authors: Danxia Deng, Chengyu Li, Zhenyuan Zheng, Bing Wen, Liandi Liao, Enmin Li, Liyan Xu
Journal: Cancer Research (2023)

Abstract Proteins containing a CAAX motif at the C-terminus can occur prenylation modification and regulate the localization and activity of a series of key regulatory proteins, including RAS superfamily members, heterotrimeric G proteins, nuclear lamina protein, and several protein kinases and phosphatases. However, studies of prenylated proteins in esophageal cancer are limited. Here, we found that paralemmin-2 (PALM2), a potential prenylated protein, was up-regulated and associated with a poor prognosis of patients, through research on large-scale proteomic data of esophageal cancer in our laboratory. The low throughput verification also showed that the expression of PALM2 in esophageal cancer tissues was higher than that in their paired normal esophageal epithelial tissues, and it was generally expressed in the membrane and cytoplasm of esophageal squamous cancer cells (ESCC). PALM2 interacted with the two subunits of farnesyl transferase (FTase), FNTA and FNTB. The FTase inhibitor weakened the membranous location of PALM2 and mutation in the CAAX motif of PALM2 (PALM2C408S) impaired its membranous localization, indicating PALM was prenylated by FTase. Overexpressed PALM2 promoted the migration of cancer cells, whereas PALM2C408S lost this ability. Mechanistically, PALM2 interacted with the N-terminal FERM domain of ezrin of Ezrin/Radixin/Moesin (ERM) family dependent on its prenylation. The mutagenesis indicated that lysine residues K253/K254/K262/K263 in ezrin’s FERM domain and cysteine residue C408 in PALM2’s CAAX motif were important for their interaction and ezrin activation. The knockout of ezrin prevented enhanced cancer cell migration by PALM2 overexpression. PALM2, depending on its prenylation, made ezrin get more membranous distribution and increased the phosphorylation of ezrin Y146 site. In summary, prenylated PALM2 promoted the migration of cancer cells through activating ezrin. (This work was supported by the National Natural Science Foundation of China (82173034, 81172264), and Innovative Team Grant of Guangdong Department of Education (2021KCXTD005)). Citation Format: Danxia Deng, Chengyu Li, Zhenyuan Zheng, Bing Wen, Liandi Liao, Enmin Li, Liyan Xu. Prenylated PALM2 promotes the migration of esophageal squamous cancer cells through activating ezrin. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3610.